Endopeptidase 24.11, which is one of neutral endopeptidases, is metal-containing neutral peptidase which is required to contain zinc in its active center and it is also called enkephalinase or an antigen of acute lymphoblast leukemia (CD10).
Endopeptidase 24.11 is an enzyme which distributes widely, for example, in kidney, lung, central nervous system, intestinal canal, neutrophil, fibroblast, vascular endothelial cell, etc. and hydrolyzes many physiologically active peptides such as artial natriuretic polypeptide (ANP), enkephaline, bradykinin and substance P. Therefore, endopeptidase 24.11 is known to take part in various biological functions and to exhibit various therapeutic effects by inhibiting the above-mentioned enzymatic activity.
These effects are exemplified by an effect on cardiovascular disease such as heart failure indicating symptoms of edema and hypertension, an effect on renal disease such as renal failure indicating symptoms of edema and an increase of ascites, an effect on gastroenteric disorder such as diarrhea and hyperchlorhydria, an analgestic effect, an effect on endocrine and metabolic disease such as obesity, and an effect on autoimmune disease such as rheumatic disease.
Substances inhibiting endopeptidase 24.11 are described below in more detail.
The following effects of compounds inhibiting endopeptidase 24.11 have been observed. An increasing effect of total urine volume and urinary sodium excretion has been observed on heart failure models by rapid ventricular pacing method (J. Cardiovasc. Pharmacol., 19, 635-640 (1992)). An increasing effect of urinary ANP excretion and urinary cyclic GMP excretion has been observed (J. Pharmacol. Exp. Ther., 266, 872-883 (1993)). A hypotensive effect has been observed using spontaneously hypertensive rats or deoxycorticosteron acetate induced hypertensive rats (J. Pharmacol. Exp. Ther., 265, 1339-1347 (1993)). An increasing effect of urinary sodium excretion has been observed using rats subjected to five-sixths renal ablation (Circ. Res., 65, 640-646 (1989). An inhibitory effect, which is derived from the effect on the central nervous system, upon pentagastrin-stimulated gastric secretion has been observed (Eur. J. Pharmacol., 154, 247-254 (1988). An improvement effect of acute diarrhea caused by castor oil has been observed (Gut, 33, 753-758 (1992)). An analgestic effect has been observed by the tail-withdrawal test and the hotplate jump test (Nature, 288, 286-288 (1980). In addition, since bonbesin (Proc. Natl. Acad. Sci., 88, 10662-10666 (1991)), which is known as one of substrates of endopeptidase 24.11, has been reported to reduce food intake (J. Clin. Endocrinol. Metab., 76, 1495-1498 (1993)), a compound inhibiting endopeptidase 24.11 is expected to be a therapeutic agent for endocrine and metabolic disease such as obesity. Since an endopeptidase 24.11 activity in blood and synovial fluid has been reported to be higher in patients with rheumatoid arthritis than in healthy men and patients with osteoarthritis (Rheumatol. Int., 13, 1-4 (1993)), a compound inhibiting endopeptidase 24.11 is expected to be a therapeutic agent for autoimmune disease where an immune function is lowered such as rheumatic disease.
A structural feature of the present invention is that 1,3-dialkylurea has carboxyl groups at the ends of both alkylene chains and a hydroxyl group at one alkylene chain. Prior art is explained below from the standpoint of the chemical structure.
It has been reported that 1,3-dialkylurea derivatives wherein a carboxyl group is introduced at the end of one alkylene chain have angiotensin II antagonistic effect (Laid-open Japanese Patent Publication Nos. 6-72985 and 6-184086). It has been reported that 1,3-dialkylurea derivatives wherein carboxyl groups are introduced at the ends of both alkylene chains inhibit an angiotensin-converting enzyme (Laid-open Japanese Patent Publication No.58-55451). It has also been reported that amino acid derivatives containing a nitrogen atom located at the 3rd position of 1-(carboxyalkylamino)urea derivatives inhibit an activity of enkephalinase (Examined Japanese Patent Publication No. 3-79339). However, no reports disclose 1,3-dialkylurea derivatives wherein carboxyl groups are introduced at the ends of both alkylene chains and a hydroxyl group is introduced at one alkylene chain.
In addition, regarding 1,3-dialkylurea derivatives containing a hydroxyl group, it has been reported that polypeptide derivatives have a renin-inhibiting activity (Laid-open Japanese Patent Publication Nos. 62-33141 and 62-164658) and that amino acid derivatives inhibit rctrovirus protease such as human immunodeficiency virus protease (WO 92/08698). However, no reports disclose 1,3-dialkylurea derivatives containing a hydroxyl group wherein carboxyl groups are introduced at the ends of both alkylene chains.
As mentioned above, various studies have been made for the 1,3-dialkylurea derivatives, but no study has been made for the 1,3-dialkylurea derivatives wherein carboxyl groups are introduced at the ends of both alkylene chains and a hydroxyl group is also introduced at one alkylene chain. It was a very interesting subject to synthesize such compounds and to examine their pharmacological effects, particularly their effects on endopeptidase 24.11.
The inventors paid attention to the alkylene chain of the 1,3-dialkylurea derivatives and synthesized novel 1,3-dialkylurea derivatives wherein carboxyl groups, ester groups thereof, etc. are introduced at the ends of both alkylene chains and a hydroxyl group is also introduced at one alkylene chain to examine their pharmacological effects.
Examining the pharmacological effects by the use of N-dansyl-D-alanyl-glycyl-p-nitrophenylalanyl-glycine, which is known as a substrate of endopeptidase 24.11, the novel 1,3-dialkylurea derivatives having a hydroxyl group of the present invention were found to have high inhibitory activities on endopeptidase 24.11.